This invention relates generally to 4,4-disubstituted-3,4-dihydro-2(1H)-quinazolinones which are useful as inhibitors of HIV reverse transcriptase, pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as assay standards or reagents, and intermediates and processes for making the same.
Two distinct retroviruses, human immunodeficiency virus (HIV) type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which predisposes them to debilitating and ultimately fatal opportunistic infections.
The disease AIDS is the end result of an HIV-1 or HIV-2 virus following its own complex life cycle. The virion life cycle begins with the virion attaching itself to the host human T-4 lymphocyte immune cell through the bonding of a glycoprotein on the surface of the virion""s protective coat with the CD4 glycoprotein on the lymphocyte cell. Once attached, the virion sheds its glycoprotein coat, penetrates into the membrane of the host cell, and uncoats its RNA. The virion enzyme, reverse transcriptase, directs the process of transcribing the RNAinto single-stranded DNA. The viral RNA is degraded and a second DNA strand is created. The now double-stranded DNA is integrated into the human cell""s genes and those genes are used for virus reproduction.
At this point, RNA polymerase transcribes the integrated DNA into viral RNA. The viral RNA is translated into the precursor gag-pol fusion polyprotein. The polyprotein is then cleaved by the HIV protease enzyme to yield the mature viral proteins. Thus, HIV protease is responsible for regulating a cascade of cleavage events that lead to the virus particle""s maturing into a virus that is capable of full infectivity.
The typical human immune system response, killing the invading virion, is taxed because the virus infects and kills the immune system""s T cells. In addition, viral reverse transcriptase, the enzyme used in making a new virion particle, is not very specific, and causes transcription mistakes that result in continually changed glycoproteins on the surface of the viral protective coat. This lack of specificity decreases the immune system""s effectiveness because antibodies specifically produced against one glycoprotein may be useless against. another, hence reducing the number of antibodies available to fight the virus. The virus continues to reproduce while the immune response system continues to weaken. Eventually, the HIV largely holds free reign over the body""s immune system, allowing opportunistic infections to set in and without the administration of antiviral agents, immunomodulators, or both, death may result.
There are at least three critical points in the virus""s life cycle which have been identified as possible targets for antiviral drugs: (1) the initial attachment of the virion to the T-4 lymphocyte or macrophage site, (2) the transcription of viral RNA to viral DNA (reverse transcriptase, RT), and (3) the processing of gag-pol protein by HIV protease.
Inhibition of the virus at the second critical point, the viral RNA to viral DNA transcription process, has provided a number of the current therapies used in treading AIDS. This transcription must occur for the virion to reproduce because the virion""s genes are encoded in RNA and the host cell reads only DNA. By introducing drugs that block the reverse transcriptase from completing the formation of viral DNA, HIV-1 replication can be stopped.
A number of compounds that interfere with viral replication have been developed to treat AIDS. For example, nucleoside analogs, such as 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT), 2xe2x80x2,3xe2x80x2-dideoxycytidine (ddC), 2xe2x80x2,3xe2x80x2-dideoxythymidinene (d4T), 2xe2x80x2,3xe2x80x2-dideoxyinosine (ddI), and 2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-thia-cytidine (3TC) have been shown to be relatively effective in halting HIV replication at the reverse transcriptase (RT) stage.
An active area of research is in the discovery of non-nucleoside HIV reverse transcriptase inhibitors. As an example, it has been found that certain benzoxazinones and quinazolinones are active in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS.
U.S. Pat. No. 5,519,021 describe reverse transcriptase inhibitors which are benzoxazinones of the formula: 
wherein X is a halogen, Z may be O.
EP 0,530,994 and WO 93/04047 describe HIV reverse transcriptase inhibitors which are quinazolinones of the formula A: 
wherein G is a variety of groups, R3 and R4 may be H, Z may be O, R2 may be unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl, unsubstituted heterocycle, and optionally substituted aryl, and R1 may be a variety of groups including substituted alkyl.
WO 95/12583 also describes HIV reverse transcriptase inhibitors of formula A. In this publication, G is a variety of groups, R3 and R4 may be H, Z may be O, R2 is substituted alkenyl or substituted alkynyl, and R1 is cycloalkyl, alkynyl, alkenyl, or cyano. WO 95/13273 illustrates the asymmetric synthesis of one of the compounds of WO 95/12583, (S)-(xe2x88x92)-6-chloro-4-cyclopropyl-3,4-dihydro-4((2-pyridy)ethynyl)-2(1H)-quinazolinone.
Synthetic procedures for making quinazolinones like those described above are detailed in the following references: Houpis et al, Tetr. Lett. 1994, 35(37), 6811-6814; Tucker et al, J. Med. Chem. 1994, 37, 2437-2444; and, Huffman et al, J. Org. Chem. 1995, 60, 1590-1594.
DE 4,320,347 illustrates quinazolinones of the formula: 
wherein R is a phenyl, carbocyclic ring, or a heterocyclic ring. Compounds of this sort are not considered to be part of the present invention.
Even with the current success of reverse transcriptase inhibitors, it has been found that HIV patients can become resistant to a single inhibitor. Thus, it is desirable to develop additional inhibitors to further combat HIV infection.
Accordingly, one object of the present invention is to provide novel reverse transcriptase inhibitors.
It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.
It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need thereof a therapeutically effective combination of (a) one of the compounds of the present invention and (b) one or more compounds selected form the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
It is another object of the present invention to provide pharmaceutical compositions with reverse transcriptase inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.
It is another object of the present invention to provide a method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of the present invention.
It is another object of the present invention to provide a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
wherein R1, R2, R3, and R8 are defined below, stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, are effective reverse transcriptase inhibitors.
[1] Thus, in a first embodiment, the present invention provides a novel compound of formula I: 
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
R1 is C1-3 alkyl substituted with 1-7 halogen;
R2 is selected from C1-5 alkyl substituted with 1-2 R4, C2-5 alkenyl substituted with 1-2 R4, and C2-5 alkynyl substituted with 1 R4;
R3, at each occurrence, is independently selected from C1-4 alkyl, OH, C1-4 alkoxy, F, Cl, Br, I, NR5R5a, NO2, CN, C(O)R6, NHC(O)R7, and NHC(O)NR5R5a;
alternatively, if two R3""s are present and are attached to adjacent carbons, then they may combine to form xe2x80x94OCH2Oxe2x80x94;
R4 is selected from C3-5 cycloalkyl substituted with 0-2 R3, phenyl substituted with 0-5 R3, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-2 R3;
R5 and R5a are independently selected from H and C1-3 alkyl;
R6 is selected from H, OH, C1-4 alkyl, C1-4 alkoxy, and NR5R5a;
R7 is selected from C1-3 alkyl and C1-3 alkoxy;
R8 is selected from H, C3-5 cycloalkyl, and C1-3 alkyl; and,
n is selected from 0, 1, 2, 3, and 4.
[2] In a preferred embodiment, the present invention provides a novel compound of formula I, wherein:
R1 is C1-3 alkyl substituted with 1-7 halogen;
R2 is selected from C1-5 alkyl substituted with 1 R4, C2-5 alkenyl substituted with 1 R4, and C2-5 alkynyl substituted with 1 R4;
R3, at each occurrence, is independently selected from C1-4 alkyl, OH, C1-4 alkoxy, F, Cl, Br, I, NR5R5a, NO2, CN, C(O)R6, NHC(O)R7, and NHC(O)NR5R5a;
alternatively, if two R3""s are present and are attached to adjacent carbons, then they may combine to form xe2x80x94OCH2Oxe2x80x94;
R4 is selected from C3-5 cycloalkyl substituted with 0-2 R3, phenyl substituted with 0-2 R3, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R3;
R5 and R5a are independently selected from H, CH3 and C2H5;
R6 is selected from H, OH, CH3, C2H5, OCH3, OC2H5, and NR5R5a;
R7 is selected from CH3, C2H5, OCH3, and OC2H5;
R8 is selected from H, cyclopropyl, CH3 and C2H5; and,
n is selected from 0, 1, 2, and 3.
[3] In a more preferred embodiment, the present invention provides a novel compound of formula I, wherein:
R1 is selected from CF3, and C2F5;
R2 is selected from C1-3 alkyl substituted with 1 R4, C2-3 alkenyl substituted with 1 R4, and C2-3 alkynyl substituted with 1 R4;
R3, at each occurrence, is independently selected from C1-3 alkyl, OH, C1-3 alkoxy, F, Cl, Br, I, NR5R5a, NO2, CN, C(O)R6, NHC(O)R7, and NHC(O)NR5R5a;
alternatively, if two R3""s are present and are attached to adjacent carbons, then they may combine to form xe2x80x94OCH2Oxe2x80x94;
R4 is selected from C3-5 cycloalkyl substituted with 0-2 R3, phenyl substituted with 0-2 R3, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R3;
R5 and R5a are independently selected from H, CH3 and C2H5;
R6 is selected from H, OH, CH3, C2H5, OCH3, OC2H5, and NR5R5a;
R7 is selected from CH3, C2H5, OCH3, and OC2H5;
R8 is selected from H, CH3 and C2H5; and,
n is selected from 0, 1, and 2.
[4] In an even more preferred embodiment, the present invention provides a novel compound of formula I, wherein:
R1 is CF3;
R2 is selected from C1-3 alkyl substituted with 1 R4, C2-3 alkenyl substituted with 1 R4, and C2-3 alkynyl substituted with 1 R4;
R3, at each occurrence, is independently selected from C1-3 alkyl, OH, C1-3 alkoxy, F, Cl, NR5R5a, NO2, CN, C(O)R6, NHC(O)R7, and NHC(O)NR5R5a;
alternatively, if two R3""s are present and are attached to adjacent carbons, then they may combine to form xe2x80x94OCH2Oxe2x80x94;
R4 is selected from cyclopropyl substituted with 0-1 R3, phenyl substituted with 0-2 R3, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-1 R3, wherein the heterocyclic system is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-oxazolyl, 2-thiazolyl, 4-isoxazolyl, and 2-imidazolyl;
R5 and R5a are independently selected from H, CH3 and C2H5;
R6 is selected from H, OH, CH3, C2H5, OCH3, OC2H5, and NR5R5a;
R7 is selected from CH3, C2H5, OCH3, and OC2H5;
R8 is selected from H, CH3 and C2H5; and,
n is selected from 1 and 2.
[5] In a further preferred embodiment, wherein the compound is of formula Ia 
[5] In a further preferred embodiment, wherein the compound is of formula Ib: 
[7] In a further preferred embodiment, the compound of formula I is selected from:
(+/xe2x88x92)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-6-Chloro-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-6-Chloro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-4-Cyclopropylethynyl-6-methoxy-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-6-Methoxy-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-6-Methoxy-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-4-Cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-5,6-Difluoro-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-5,6-Difluoro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-4-Cyclopropylethynyl-6-fluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-6-Fluoro-4-(2-pyridyl)ethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-6-Fluoro-4-phenylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-6-Fluoro-4-(2xe2x80x2-2-pyridyl)ethyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-6-Fluoro-4-phenylethyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(xe2x88x92)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+)-6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+)-4-Cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(xe2x88x92)-4-Cyclopropylethynyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+)-4-E-Cyclopropylethenyl-5,6-difluoro-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; and,
(xe2x88x92)-6-Chloro-4-E-cyclopropylethenyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
or a pharmaceutically acceptah salt thereof.
[8] In a second embodiment, the present invention provides a novel compound of formula II: 
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
R2 is Cxe2x89xa1Cxe2x80x94R4a;
R3 is selected from C1-4 alkyl, OH, C1-4 alkoxy, F, Cl, Br, I, NR5R5a, NO2, CN, C(O)R6, NHC(O)R7, and NHC(O)NR5R5a;
R4a is selected from methyl, ethyl, n-propyl, i-propyl, i-butyl, t-butyl, and i-pentyl;
R5 and R5a are independently selected from H and C1-3 alkyl;
R6 is selected from H, OH, C1-4 alkyl, C1-4 alkoxy, and NR5R5a;
R7 is selected from C1-3 alkyl and C1-3 alkoxy;
R8 is selected from H, C3-5 cycloalkyl, and C1-3 alkyl; and,
n is selected from 0, 1, 2, 3, and 4.
[9] In another preferred embodiment, the present invention provides a novel compound of formula II, wherein:
R2 is Cxe2x89xa1Cxe2x80x94R4a;
R3 is selected from C1-4 alkyl, OH, C1-4 alkoxy, F, Cl, Br, I, NR5R5a, NO2, CN, C(O)R6, and NHC(O)R7;
R4a is selected from methyl, ethyl, n-propyl, i-propyl, i-butyl, t-butyl, and i-pentyl;
R5 and R5a are independently selected from H, CH3 and C2H5;
R6 is selected from H, OH, CH3, C2H5, OCH3, OC2H5, and NR5R5a;
R7 is selected from CH3, C2H5, OCH3, and OC2H5;
R8 is selected from H, cyclopropyl, CH3 and C2H5; and,
n is selected from 0, 1, and 2.
[10] In a further preferred embodiment, wherein the compound is of formula IIa 
[11] In a further preferred embodiment, wherein the compound is of formula Ilb: 
[12] In another more preferred embodiment, the compound of formula II is selected from:
(+/xe2x88x92)-6-Chloro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-6-Chloro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-4-Isopropylethynyl-6-methoxy-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-5,6-Difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-5,6-Difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-5,6-Difluoro-4-isopentyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-6-Fluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+/xe2x88x92)-6-Fluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(xe2x88x92)-5,6-Difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(+)-5,6-Difluoro-4-isopropylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
(xe2x88x92)-5,6-Difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone; and,
(+)-5,6-Difluoro-4-ethylethynyl-4-trifluoromethyl-3,4-dihydro-2(1H)-quinazolinone;
or a pharmaceutically acceptable salt thereof.
In a third embodiment, the present invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or II or pharmaceutically acceptable salt form thereof.
In a fourth embodiment, the present invention provides a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of formula I or II or pharmaceutically acceptable salt form thereof.
In a fifth embodiment, the present invention provides a novel method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:
(a) a compound of formula I or II; and,
(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
In another preferred embodiment, the reverse transcriptase inhibitor is selected from AZT, 3TC, ddI, ddC, d4T, delavirdine, TIBO derivatives, BI-RG-587, nevirapine, L-697,661, LY 73497, Ro 18,893, loviride, trovirdine, MKC-442, and HBY 097, and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478, nelfinavir, KNI-272, CGP-61755, U-140690, and ABT-378.
In an even more preferred embodiment, the reverse transcriptase inhibitor is selected from AZT and 3TC and the protease inhibitor is selected from saquinavir, ritonavir, nelfinavir, and indinavir.
In a still further preferred ebodiment, the reverse transcriptase inhibitor is AZT.
In another still further preferred embodiment, the rotease inhibitor is indinavir.
In a sixth embodiment, the present invention provides a pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of:
(a) a compound of formula I or II; and,
(b) at least one compound selected, from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers.
In a seventh embodiment, the present invention provides a novel method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of formula I or II.
In a eighth embodiment, the present invention to provides a novel a kit or container comprising a compound of formula I or II in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.
As used herein, the following terms and expressions have the indicated meanings. It will be appreciated that the compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
The processes of the present invention are contemplated to be practiced on at least a multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilogram of at least one starting material is used. Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl; t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentaf luoroethyl, and pentachloroethyl; xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. Alkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo and iodo. xe2x80x9cCounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
As used herein, xe2x80x9carylxe2x80x9d or xe2x80x9caromatic residuexe2x80x9d is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as phenyl or naphthyl. As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3- to 5-membered monocyclic ring, which may be saturated or partially unsaturated. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5- to 6-membered monocyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a stable 5- to 6-membered monocyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 3 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 2-pyrrolidonyl, 2H-pyrrolyl, 4-piperidonyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, xe2x80x9cHIV reverse transcriptase inhibitorxe2x80x9d is intended to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT). Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, ddI, d4T, and 3TC. Examples of non-nucleoside RT inhibitors include, but are no limited to, delavirdine (Pharmacia and Upjohn U90152S), TIBO derivatives, BI-RG-587, nevirapine (Boehringer Ingelheim), L-697,661, LY 73497, Ro 18,893 (Roche), loviride (Janssen), trovirdine (Lilly), MKC-442 (Triangle), and HBY 097 (Hoechst).
As used herein, xe2x80x9cHIV protease inhibitorxe2x80x9d is intended to refer to compounds which inhibit HIV protease. Examples include, but are not limited, saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), VX-478 (Vertex/Glaxo Wellcome), nelfinavir (Agouron, AG-1343), KNI-272 (Japan Energy), CGP-61755 (Ciba-Geigy), U-140690 (Pharmacia and Upjohn), and ABT-378. Additional examples include the cyclic protease inhibitors disclosed in WO93/07128, WO 94/19329, WO 94/22840, and PCT Application Number US96/03426.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxyymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of.which is hereby incorporated by reference.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) or other formulas or compounds of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the present invention, for example formula (I), are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein the hydroxy or amino group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl or free amino, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention, and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contemplated by the present invention.
xe2x80x9cSubstitutedxe2x80x9d is intended to indicate that one or more hydrogens on the atom indicated in the expression using xe2x80x9csubstitutedxe2x80x9d is replaced with a selection from the indicated group(s), provided that the indicated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O) group, then 2 hydrogens on the atom are replaced.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Each of the references cited below are hereby incorporated herein by reference. 
Scheme 1 illustrates a method of preparing keto-anilines from an appropriately substituted 2-aminobenzoic acid. The acid is converted to its N-methoxy-N-methyl amide derivative which can then be displaced to obtain the R1-substituted ketone. The keto-anilines are useful intermediates for the presently claimed compounds. 
Scheme 2 describes another method of preparing keto-anilines, this time from an appropriately substituted aniline. After iodination and amine protection, a group such as trifluoromethyl can be introduced using a strong base and ethyl trifluoroacetate. Deprotection provides the keto-aniline. Additional means of preparing keto-anilines are known to one of skill in the art, e.g, Houpis et al, Tetr. Lett. 1994, 35(37), 6811-6814, the contents of which are hereby incorporated herein by reference. 
Another method of making 2-trifluoroacetylanilines is shown in Scheme 3. After forming the protected aniline, the amide is then reduced and the trifluoromethyl group added. Oxidation with an oxidant, such as MnO2, provides the useful intermediate. 
Using the general method detailed in Scheme 4, one can prepare compounds of the present invention. Keto-aniline 1, which may be prepared by the methods desribed in Schemes 1 and 2, is treated with trimethylsilyl isocyanate in dry tetrahydofuran in the presence of dimethylaminopyridine followed by tetrabutylammonium fluoride to give the hydroxy-urea 2. The hydroxy-urea 2 is then dehydrated with a dehydrating agent such as 4 xc3x85 molecular sieves in refluxing toluene or xylenes to give the ketimine 3. A substituted acetylenic R2 group is added by treating the ketimine 3 with a lithium acetylide, which is prepared in a separate vessel by reacting the corresponding substituted acetylene with n-butyllithium in dry tetrahydrofuran, to give the 4,4-disubstituted 3,4-dihydro-2(1H)-quinazolinone 4, a compound of formula I. The acetylenic bond of the compound 4 may be reduced, e.g., by catalytic hydrogenation, to give the corresponding alkenyl group (not shown) or the saturated compound 5.
Other R2 groups may also be introduced by directly reacting the imine 3 with a lithiate R2Li or a Grignard reagent R2MgX in the presence or absence of Lewis acid catalyst, such as BF3 etherate. See also Huffman et al, J. Org. Chem. 1995, 60, 1590-1594, the contents of which are hereby incorporated herein by reference.
In certain instances, one enantiomer of a compound of Formula I or II may display superior activity compared with the other. When required, separation of the racemic material can be achieved by HPLC using a chiral column as exemplified in Examples 27-34 (Scheme 4) or by a resolution using a resolving agent such as camphonic chloride as in Thomas J. Tucker, et al, J. Med. Chem. 1994, 37, 2437-2444. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g. Mark A. Huffman, et al, J. Org. Chem. 1995, 60, 1590-1594.